Radiofrequency ablation is an inferior option to liver resection for solitary hepatocellular carcinoma ≤5 cm without cirrhosis: A population-based study with stratification by tumor size

Song-Chen Dong ,Dou-Sheng Bi ,Fu-An Wng ,Sheng-Jie Jin ,Chi Zhng ,Bo-Hun Zhou ,Guo-Qing Jing ,

a Department of Hepatobiliary Surgery,Clinical Medical College,Yangzhou University,Yangzhou 225001,China

b Department of Hepatobiliary Surgery,The First Clinical College,Dalian Medical University,Dalian 1160 0 0,China

c Department of Interventional Radiology,Clinical Medical College,Yangzhou University,Yangzhou 225001,China

Keywords: Cirrhosis Liver resection Radiofrequency ablation Hepatocellular carcinoma Tumor size

ABSTRACT Background: About 10%-20% of all individuals who develop hepatocellular carcinoma (HCC) do not have cirrhosis.Comparisons are rarely reported regarding the effectiveness of radiofrequency ablation (RFA)and liver resection (LR) in survival of HCC without cirrhosis and stratification by tumor size ≤5 cm.Methods: We used the Surveillance,Epidemiology,and End Results (SEER) database and identified 1505 patients with a solitary HCC tumor ≤5 cm who underwent RFA or LR during 2004-2015.Patients were classified into non-cirrhosis and cirrhosis groups and each group was categorized into three subgroups,according to tumor size (≤30 mm,31-40 mm,41-50 mm).Results: In patients without cirrhosis,LR showed better 5-year HCC cancer-specific survival than RFA in all tumor size subgroups (≤30 mm: 82.51% vs.56.42%;31-40 mm: 71.31% vs.46.83%;41-50 mm:74.7% vs.37.5%;all P <0.05).Compared with RFA,LR was an independent protective factor for HCC cancer-specific survival in multivariate Cox analysis [≤30 mm: hazard ratio (HR)=0.533,95% confidence interval (CI): 0.313-0.908;31-40 mm: HR=0.439,95% CI: 0.201-0.957;41-50 mm: HR=0.382;95% CI:0.159-0.916;all P <0.05].In patients with cirrhosis,for both tumor size ≤30 mm and 31-40 mm groups,there were no significant survival differences between RFA and LR in multivariate analysis (all P >0.05).However,in those with tumor size 41-50 mm,LR showed significantly better 5-year HCC cancer-specific survival than RFA in both univariate (54.72% vs.23.06%;P <0.001) and multivariate analyses (HR=0.297;95% CI: 0.136-0.648;P=0.002).Conclusions: RFA is an inferior treatment option to LR for patients without cirrhosis who have a solitary HCC tumor ≤5 cm.

Introduction

Hepatocellular carcinoma (HCC),which represents approximately 90% of primary liver cancers,is ranked the sixth most frequently diagnosed tumor and the fourth leading cause of cancerrelated death worldwide [1,2].In recent years,the number of HCC cases has increased substantially,and the age-adjusted death rate has increased annually by 2.1% [3].Therefore,choosing the best curative treatment option has become not only a clinical issue but also a therapeutic challenge for most surgeons.According to current studies,the recommended treatment options for patients with a solitary nodule ≤5 cm,or no more than three nodules each ≤3 cm in size without evidence of vascular invasion or metastasis,include radiofrequency ablation (RFA),liver resection (LR),and liver transplantation (LT).LT is more effective than RFA and LR at the very-early-tumor and early-tumor stages [1,4-6].However,LR and RFA are widely adopted in therapy for patients with HCC,owing to the lack of liver donors,high medical costs,and incomplete distribution system for LT [7,8].

HCC mostly occurs underlying cirrhosis.However,approximately 10%-20% of all HCC individuals develop with non-cirrhotic liver [9].Many recent studies have compared the clinical effectiveness of RFA and LR according to different tumor sizes.However,the findings remain controversial and there is no consensus to date regarding whether RFA can serve as an appropriate alternative to LR in terms of efficacy.Some studies have reported similar survival for RFA and LR with a solitary HCC lesion ≤3 cm [10–12],whereas others demonstrated that LR is superior to RFA in terms of survival,regardless of tumor size [13,14].These inconsistent conclusions may be owing to existing heterogeneities in study subgroups.It is worth noting that there are heterogeneities in not only pathophysiology but also HCC biological characteristics between cirrhosis and non-cirrhosis [15,16].Therefore,when analyzing the effi-cacy of LR in comparison with RFA for HCC,the presence or absence of cirrhosis is an important inclusion criterion for patient subgroups to ensure homogeneity.Until now,the difference in efficacy between LR and RFA in HCC stratified by tumor size with and without cirrhosis remains unclear.In this study,we used the Surveillance,Epidemiology,and End Results (SEER) database to examine the effectiveness of LR and RFA on survival outcomes in patients with HCC ≤5 cm,using stratification based on the presence or absence of cirrhosis and according to different tumor sizes.

Patients and methods

Patient selection

This retrospective cohort study was conducted using data from the SEER Program (www.seer.cancer.gov),maintained by the National Cancer Institute and representing a clustering of population-based cancer registries.The SEER database is published annually and includes cancer incidence and survival data.We used SEER∗Stat 8.3.8 software to collect data of patients with a histopathological diagnosis of liver cancer between 2004 and 2015,identified using International Classification of Diseases for Oncology,Third Edition (ICD-O-3) codes 8170/3-8175/3.We extracted demographic data including sex,age at diagnosis,race,marital status,year of diagnosis,pathological grade,tumor size,tumornode-metastasis (TNM) stage,alpha-fetoprotein (AFP) level,fibrosis score,surgery,chemotherapy,radiotherapy,total number ofinsitu/malignant tumors,SEER cause-specific death classification,SEER other cause of death classification,vital status,and survival months.The following inclusion criteria were used: (i) received RFA (SEER code: 16) or LR (SEER code: 20-26,30,36-38,50-52,59,60,66,90) as primary treatment;(ii) fibrosis score (SEER code: 0,1);(iii) stage T1.Exclusion criteria were as follows: (i) tumor size>5 cm;(ii) history of another malignancy or secondary primary malignancy;(iii) regional lymph node metastasis (N1);(iv) distant metastasis was apparent (M1);(v) unknown or cannot evaluated N and/or M category.Ultimately,1505 patients from the database were included in the analysis.

The SEER database classifies fibrosis according to scores defined by the American Joint Committee on Cancer (AJCC) [17].In this study,we defined “0 to 4 (undetectable to moderate fibrosis)” and“5 to 6 (incomplete to complete cirrhosis)” as “no cirrhosis” and“cirrhosis”,respectively.

Statistical analysis

In this study,eligible patients with HCC were divided into the non-cirrhosis group and the cirrhosis group.Due to the uncertainty whether the results were similar between RFA and LR for tumors smaller than 30 mm,patients with tumor size ≤30 mm were established as the first subgroup in stratification by tumor size.The non-cirrhosis group and cirrhosis group were each divided into three tumor-size groups: ≤30 mm,31-40 mm,and 41-50 mm.We compared the demographic and cancer characteristics of patients who received RFA and LR using Chi-square test separately for the two groups.HCC cancer-specific survival (HCSS) was defined as the primary endpoint.HCSS was defined as the time from the date of diagnosis to death owing to HCC.The survival rate was calculated using Kaplan-Meier analysis,and intergroup comparisons classified by tumor size were performed using log-rank test.Variables withPvalues <0.05 in Kaplan-Meier analysis were further evaluated in a multivariate Cox regression model to identify predictors of survival outcomes.Because the sample size of adjuvant radiotherapy was too small as shown in Table 1 (non-cirrhosis group,n=3;cirrhosis group,n=13),the survival analysis concerning adjuvant radiotherapy was not made.All statistical evaluations were conducted using IBM SPSS version 24 (IBM Corp.,Armonk,NY,USA).A two-sidedP<0.05 was adopted to indicate statistically significant.

Table 1Baseline demographic and tumor characteristics of patients in the SEER database.

Results

According to the selection criteria,1505 eligible patients with HCC who received LR or RFA as first-line treatment for a single lesion ≤5 cm were screened from 2004 to 2015,including 405 patients who did not have cirrhosis and 1100 who had cirrhosis(Fig.1).The baseline demographics and characteristics of the patient cohort are shown in Table 1.In the non-cirrhosis group,the subgroup that underwent RFA had a higher proportion of patients who were male,white,unmarried,with an elevated AFP level,receiving chemotherapy and HCC-specific mortality,compared with the subgroup that underwent LR.Moreover,in the cirrhosis group,the RFA subgroup had higher proportions of patients with the year of diagnosis 2012-2015,elevated AFP levels and chemotherapy.Strikingly,with subsequent years of diagnosis,the proportion of patients with cirrhosis undergoing RFA gradually increased,with statistical significance,unlike in the non-cirrhosis group.

Fig.1.CONSORT flow diagram for this study.SEER: Surveillance,Epidemiology,and End Results;AJCC: American Joint Committee on Cancer;HCC: hepatocellular carcinoma;RFA: radiofrequency ablation;LR: liver resection.

Comparison of the effect between RFA and LR on HCSS in all patients,stratified by tumor size

We identified 912 and 593 patients who underwent RFA and LR,respectively,and we analyzed HCSS between the two subgroups according to different tumor sizes (Table 2).

In the group with tumor size ≤30 mm,667 patients received RFA and 325 underwent LR.In Kaplan-Meier survival analyses and multivariate analyses with Cox regression (Table 2),sex,age,race and AFP level were independent prognostic factors and treatment modality was not observed to be an independent prognostic factor for HCSS [hazard ratio (HR)=0.830,95% confidence interval (CI):0.642-1.073,P=0.155].

Among patients with tumor size ranging from 31 to 40 mm(178 patients received RFA and 156 underwent LR) and 41 to 50 mm (67 patients received RFA and 112 underwent LR),treatment modality was an independent prognostic factor for HCSS in multivariate analysis (allP<0.05;Table 2).Furthermore,LR presented significantly superior survival compared with RFA for patients with tumors measuring 31-40 mm (HR=0.578,95% CI: 0.371-0.901,P=0.015) and 41-50 mm (HR=0.334,95% CI: 0.180-0.617,P<0.001).

Comparison of the effect between RFA and LR on HCSS in patients without cirrhosis,stratified by tumor size

A total of 138 and 267 patients without cirrhosis underwent RFA and LR,respectively,and we compared HCSS between the two subgroups among different tumor sizes (Table 3).

In the non-cirrhosis group with tumor size ≤30 mm,95 patients received RFA and 137 underwent LR.Treatment modality was an independent prognostic factor in univariate analysis and multivariate Cox regression for HCSS (Table 3).The 3-and 5-year HCSS rates were 79.77% and 56.42% for RFA,compared with 89.27%and 82.51% for LR,respectively (P=0.001;Table 4).Patients who received LR showed significantly improved survival benefits compared with those who received RFA (HR=0.533,95% CI: 0.313-0.908,P=0.021),as shown in Table 3 and Fig.2 A.In addition,age>60 years was an independent prognostic factor for HCSS as well(HR=1.843,95% CI: 1.106-3.071,P=0.019;Table 3).

Fig.2.HCC cancer-specific survival analyses following RFA versus LR,based on tumor size in patients without cirrhosis ≤30 mm (A),31-40 mm (B),41-50 mm (C) and with cirrhosis ≤30 mm (D);31-40 mm (E),and 41-50 mm (F).HCC: hepatocellular carcinoma;RFA: radiofrequency ablation;LR: liver resection.

Table 4Survival of patients by treatment group and tumor size.

Among patients with tumors ranging from 31 to 40 mm (27 patients received RFA and 71 underwent LR) and 41 to 50 mm(16 patients received RFA and 59 underwent LR),treatment modality was an independent prognostic factor in multivariate analysis (P<0.05;Table 3).LR showed significantly superior survival compared with RFA for patients with tumors measuring 31-40 mm (HR=0.439,95% CI: 0.201-0.957,P=0.038;Table 3 and Fig.2 B) and 41-50 mm (HR=0.382,95% CI: 0.159-0.916,P=0.031;Table 3 and Fig.2 C).

Comparison of the effect between RFA and LR on HCSS in patients with cirrhosis,stratified by tumor size

Among patients with cirrhosis and tumor size ≤30 mm,572 patients underwent RFA and 188 underwent LR.We found no significant differences in survival between RFA and LR,according to Kaplan-Meier survival analyses (Fig.2 D).The 3-and 5-year HCSS(77.87% vs.77.75%,64.99% vs.66.58%,P=0.975;Table 4) were similar between RFA and LR.

For tumors measuring 31-40 mm,151 patients received RFA and 85 underwent LR.The treatment modality was a significant prognostic factor for HCSS in Kaplan-Meier survival analysis,and patients with cirrhosis who received LR had better HCSS than those who underwent RFA (3-year HCSS: 73.46% vs.60.76%;5-year HCSS:63.53% vs.47.09%,P=0.026;Table 4 and Fig.2 E).Multivariate Cox regression showed that only race was an independent prognostic factor for HCSS (Table 5);the treatment modality was not an independent prognostic factor for HCSS (HR=0.694,95% CI: 0.409-1.178,P=0.176;Table 5).

Among patients with tumor diameter 41-50 mm,51 patients received RFA and 53 underwent LR.In univariate and multivariate analyses,we found that patients receiving LR had significantly better HCSS than those who underwent RFA (3-year HCSS:75.47% vs.42.83%;5-year HCSS: 54.72% vs.23.06%,P<0.001;Table 4 and Fig.2 F) and treatment modality was an independent prognostic factor for HCSS (HR=0.297,95% CI: 0.136-0.648,P=0.002;Table 5).Besides,marital status was also an independent prognostic factor for HCSS (non-married,HR=2.211,95%CI: 1.208-4.046;unknown,HR=27.116,95% CI: 4.490-163.750;P<0.001;Table 5).

Discussion

RFA has become the first therapeutic option for a single tumor≤5 cm or three nodules each ≤3 cm (very-early-stage and earlystage HCC) according to the Barcelona Clinical Liver Cancer (BCLC)guidelines [18].However,it is reported that RFA also has the drawback of a higher incidence of recurrence compared with LR for patients with very-early-stage and early-stage HCC [19,20].Therefore,it remains controversial whether RFA or LR is the best approach for patients with HCC.Gory et al.found no difference in the median survival between patients with ≤3 cm HCC who received LR or RFA [21].The result was consistent with our study,when we did not group patients with HCC according to the presence or absence of cirrhosis.

Numerous studies have compared the clinical value of LR and RFA in HCC [21,22],but few reports have conducted further analysis with stratification according to the presence of cirrhosis.It is widely acknowledged that cirrhosis is a significant risk factor for the development of HCC;however,10%-20% of HCC cases develop without cirrhosis [16].Different pathophysiology exists between a cirrhotic and non-cirrhotic liver.First,distinct from noncirrhosis,pseudolobules are formed in cirrhosis.Second,cirrhosis is accompanied by portal hypertension.Furthermore,most patients with cirrhosis have splenomegaly with a reduction in platelets,red blood cells,and white blood cells owing to hypersplenism.And simultaneously,different tumor biology characteristics exist between cirrhosis and non-cirrhosis.New findings have revealed that patients without cirrhosis are significantly more prone to having worse pathological stage,poor differentiation,lar ger tumor size,more lymph nodes,and distant metastases than those with cirrhosis [16].Accordingly,it is important to distinguish noncirrhosis/cirrhosis when investigating and comparing the curative effect of RFA or LR in HCC.To further analyze survival after RFA and LR,it is vital to confirm whether cirrhosis is present when diagnosing patients with HCC.

The primary purpose of the present study was to gain insight into the influence of the presence or absence of cirrhosis on treatment choice.Several studies have analyzed the therapeutic effect of LR and RFA in patients with small HCC with cirrhosis [23,24].However,few studies to date have focused on patients without cirrhosis.Our results indicated that when not classifying according to the presence or absence of cirrhosis,RFA did not differ significantly with respect to survival compared with LR among patients with HCC and tumor size ≤30 mm.However,RFA showed worse HCSS than LR with tumors measuring 31-40 mm and 41-50 mm.These results are in line with those of Gory et al.[21]and Zheng et al.[22].

In patients with cirrhosis,we did not observe survival differences between the RFA and LR cohorts with tumor size <40 mm.This result demonstrates that RFA may serve as an effective and safe alternative to LR in these patients.Among groups with tumor diameter 41-50 mm,patients who received LR showed a distinct survival advantage over those who underwent RFA.We believe that our findings are more convincing than those of Guglielmi (n=200) [25]and Desiderio (n=96) [26]as the sample size in our study was large (n=1100).Additionally,we established more reasonable grouping,not only according to tumor size but also according to the presence or absence of cirrhosis.Moreover,in cirrhosis with biggest tumor size group (41-50 mm),married showed better HCSS than non-married.This outcome may be due to the following reasons.First,married may get more psychosocial support from their partner and social support,and may display to more optimistic than do their widowed counterparts [27].Thus,married are more willing to received adjuvant therapy and improve adherence to adjuvant therapy plans.Second,decreased psychosocial support and increased psychological stress in widowed caused weakened immune function and in this way,may lead to tumor progression and mortality [28–30].Third,the larger the tumor,the higher the probability of adjuvant therapy.Compared with tumor size ≤ 30 mm and 31-40 mm groups,41-50 mm groups are more prone to receive adjuvant therapy.Thus,in 41-50 mm group,married are better able to display their advantage concerning adjuvant therapy.Therefore,marital status can play a great impact to cirrhosis patients.Finally,it has been reported in a previous study that patients without cirrhosis are significantly more prone to worse tumor biological characteristics than those with cirrhosis [16].

In patients without cirrhosis,multivariate analysis with Cox regression showed that those who received LR had an obvious survival advantage over those who underwent RFA in all patients.There are several possible reasons for the results in patients without cirrhosis showing interesting differences from those in patients with cirrhosis,as follows.

Firstly,RFA is a well-established technique using the conversion of high-frequency current into thermal energy on the electrode to directly disrupt the tumor tissue.Thus,the generated thermal energy could cause liver lesion dehydration around the electrode,which can lead to impedance so that the continual delivery of thermal energy becomes harder in non-cirrhotic liver,which is more susceptible to dehydration than a cirrhotic liver;this may be due to that a non-cirrhotic liver can hold more moisture than one affected by cirrhosis [31].Therefore,the efficiency of RFA in noncirrhosis may be lower than that in cirrhosis.

Secondly,it is generally known that hematogenous metastasis is a primary pathway in HCC.The RFA procedure could increase the intratumor pressure,which may increase the risk of hematogenous metastasis.In view of the different pressures on the portal vein between non-cirrhosis and cirrhosis,there is a greater likelihood of tumor cell diffusion to the portal vein in HCC without cirrhosis than in those with cirrhosis when RFA is performed.

Thirdly,according to a study by Di Martino et al.,a noncirrhotic liver might have not only more intrahepatic micrometastases than a cirrhotic liver but also more microvascular invasions around the tumor,which are not observed on imaging examination [32].As mentioned above,RFA showed poorer efficacy in non-cirrhosis than in cirrhosis.Hence,in patients without cirrhosis,RFA may have a poorer therapeutic effect in comparison with in patients who have cirrhosis.Moreover,surgeons can perform wider resection around the tumor with normal liver tissue in patients with HCC who do not have cirrhosis because the function of liver remnant is better in normal liver tissue than that in cirrhosis.This may lead to resection of more potential or invisible intrahepatic micrometastases and microvascular invasions in non-cirrhosis than in cirrhosis.That is,LR might be more appropriate and have greater advantages in patients without cirrhosis.

Finally,the “oven effect” theory presented by Liu et al.strongly demonstrates that RFA yields better efficacy in patients with cirrhosis than in those without cirrhosis [33].This theory relies upon the assumption that during RFA with HCC in a cirrhotic liver,a higher ablation temperature is observed because the surrounding cirrhotic liver tissue may insulate the primary hepatic tumor from the thermal energy.On the contrary,the “oven effect” is poorer in a non-cirrhotic liver.Overall,LR would have a better outcome versus RFA in patients without cirrhosis.

The present study showed that race was an independent prognostic factor for HCSS.This phenomenon may be due to race inequity in medical treatment and organ distribution.In addition,the present study also found that patients >60 years old showed worse HCSS than youngsters.Similar outcomes were found in previous studies concerning liver,colorectal and thyroid cancer [34–36].It may be mainly due to the older with the worse general health and more chronic conditions.

Several potential limitations should be acknowledged with respect to the present study.First,the SEER database lacks detailed information regarding RFA,including the type of RFA device and electrodes,the power of radiofrequency energy,and the approach of RFA (laparoscopic or percutaneous).Second,information on postoperative recurrence is unknown.Therefore,it is unclear whether poorer HCSS is associated with a higher incidence of tumor recurrence.Third,owing to limited information regarding fibrosis in the SEER database,a more detailed analysis was not possible.Finally,information regarding liver function (Child-Pugh classification,bilirubin,albumin,and globulin),surgical margin status,and comorbidities were unavailable.Differences between the two groups in terms of these factors would influence patients’ prognoses.

In conclusion,for patients without cirrhosis and a solitary HCC tumor ≤5 cm,RFA was an inferior treatment option versus LR.In patients with cirrhosis,RFA could be an effective alternative treatment with tumor size ≤40 mm,and LR is the preferred option with tumor size >40 mm.Thus,distinguishing whether patients with solitary small HCC have cirrhosis is necessary to select the best treatment and achieve a better therapeutic effect and survival.

Acknowledgments

None.

CRediTauthorshipcontributionstatement

Song-ChenDong:Conceptualization,Data curation,Formal analysis,Writing -original draft,Writing -review &editing.Dou-ShengBai:Conceptualization,Supervision,Writing -original draft,Writing -review &editing.Fu-AnWang:Investigation,Methodology,Project administration,Resources,Writing -original draft.Sheng-JieJin:Resources,Software,Validation,Visualization.Chi Zhang:Formal analysis,Methodology.Bao-HuanZhou:Data curation,Resources.Guo-QingJiang:Conceptualization,Formal analysis,Funding acquisition,Supervision,Writing -review &editing.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82173353) and Top talent scientific research project of “six one projects” (LGY2018028).

Ethicalapproval

This study was approved by the Ethics Committee of our hospital.Data were obtained from Surveillance,Epidemiology,and End Results Program (SEER),a publicly open database resource.

Competinginterest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.